Expect to regularly make a trip to the game's wiki or use mods for this game, because it has more than a few areas where you'll be left in the dark on how to proceed.
- For a start, there's knowing what each item does. A lot of them have meaningless descriptions like "???" or "It's a mystery" or "There might be options", which tells you nothing about what the item does. If the item's effect isn't obvious, then it can be impossible to work out what it actually does without looking it up. This becomes a problem when you're faced with a choice between multiple items and you have to work out which one will be most beneficial to you. The issue is so bad that many people play with a mod that gives a description of each item so they don't have to pause the game to look at the wiki every five minutes. Repentance rewrites many item descriptions to hint at their function more directly, though since they all need to be short and snappy, it doesn't help that much.
- Unlocking The Halo. You have to use The Bible on either the Mom fight or the Mom's Heart fight, which will instantly kill the boss and unlock the item. The problem is that you would never randomly use The Bible on those fights (its normal effect is just to grant flight for one room, which isn't particularly useful against them). The only in-game hint this exists is a Bible falls on Mom and kills her in a cutscene, but it's still the only item in the game with this special condition.
- The Halo is far from the worst of these obscure unlock conditions. Other achievements require you to do things like use Pandora's Box in the Dark Room (where it gives you nothing), beat the Lamb without picking up hearts, bombs and coins for the entire run, beat the Lamb in under 20 minutes (a very tight time limit that is barely possible without Sequence Breaking), collect 99 coins and spend them all in a single run, spend 30 seconds twiddling your thumbs instead of attacking Baby Plum, use Telepathy for Dummies or the Magician to give yourself homing while already having homing, get 10 tears up items or pills in a single run (which is pointless as it takes you way past the tears cap), and so on. You're very unlikely to stumble across these secrets in normal gameplay, and there's no indication within the game itself that they exist, so the only way to know about them is through a guide.
- Rebirth has a super-secret character that isn't even hinted at on the character screen. The Lost has an incredibly obtuse unlock, and it's entirely possible to play the entire rest of game without knowing he's there. Getting The Lost requires you to play as four characters in exact order, then die via extremely specific means, all in the course of one play session: Isaac must die to a Mulliboom in The Basement or The Cellar, then Magdalene must blow herself up with her own bomb in The Caves or The Catacombs, then Judas has to let Mom kill him (specifically Mom; dying to any one of the monsters she summons won't count), then Azazel must die to Satan. It should be noted that, with the game being as RNG-heavy as it is, it's not guaranteed Isaac will run into a Mulliboom at all, or that Maggie will have enough bombs to kill herself when she needs to. Ended up dying to anything else? Bad RNG caused you to miss the next step? Accidentally closed the game in-between steps? Whoops! Have fun doing the whole thing over from scratch!Why is it so cryptic? It's no wonder the Afterbirth DLC simplified the whole process, although it still requires an action most players won't ever think of doing: now you just have to die in a Sacrifice Room while holding the Missing Poster.
- Downplayed with Keeper, the secret character added in Afterbirth. He's unlocked by donating 1000 coins to the Greed Machine at the end of Greed Mode, which is more tedious than cryptic. The unlock for his unlock however required a real-life ARG and treasure hunt - averting the problem with The Lost getting datamined since he wasn't even in the game until the ARG was solved.
- Afterbirth+'s final update added another one with its secret character, The Forgotten. To unlock him, you have to defeat the first boss in under a minute, which will cause Mom to yell. Returning to the starting room shows the shadow of a shovel, and bombing anywhere will drop the shovel's handle. The handle is an active item that passively causes Mom to stomp you repeatedly, with the active effect of making her temporarily stop. You have to take the shovel to Boss Rush and win, which will complete it. From there, you need to take the shovel all the way to the Dark Room and use it on an innocuous patch of dirt. This also avoided the datamining problem since the devs outright announced The Forgotten, and players simply discovered the unlock method faster than it could be datamined. It helps that most of the process guides you in the right direction and you could feasibly accidentally discover the start — the only truly cryptic part is knowing you need a bomb.
- Tainted Cain is borderline unplayable without a guide due to his gimmick: He can't collect items; if he tries, they explode into pickups. He instead needs to create items himself with his Bag of Crafting. You use the bag to collect and store pickups, and when you have 8 you can craft an item based on which ones you have. More common pickups usually lead to worse items, so if you just grab everything in sight, you'll end up with a lot of bottom-tier crap like Mom's Coin Purse or Breakfast. This means to avoid being totally overwhelmed later on, you'll want to memorize (or look up) at least a few recipes for good items. And that's no small order—you can make almost every item (of which there are almost a thousand), and each item has 10 different recipes. Playing Tainted Cain without a guide? Good luck. It's theoretically possible to bumble your way into a game-breaking build without a guide, but the RNG has to align exactly in your favor.
- Unlocking the tainted characters in the first place is very cryptic. First of all, you need to begin the Ascent as the character you want to unlock the tainted version of. This requires you to find and blow up a marked skull on Depths II to get a Fool card, then fight Mom, pick up the Polaroid or Negative, use the Fool to escape and then use the Polaroid/Negative to open the Strange Door. Then once you reach Home you need to use Red Key or a cracked key on a specific part of the hallway before Mom's room. The first time you do this, Red Key will be in Mom's room, but there's no reason for you to reenter the hallway after picking it up, and even if you do you might not notice the faint red outline on the wall. The subsequent times are even more cryptic since the Red Key will no longer appear in Mom's room. Instead, you need to leave a trinket in a boss or item room before the Ascent, which will turn into a cracked key when you revisit the room. There's nothing in the game that indicates that this is possible, leading to a lot of players thinking that they can't unlock the tainted characters unless they happen to stumble upon Red Key or a naturally-generated cracked key, both of which are extremely rare.
